FDA Briefing Document

 

Blood Products Advisory Committee Meeting

January 9, 2009

 

 

 

 

 

 

 

 

 

Atryn® [antithrombin III (recombinant)]

 

GTC Biopharmaceuticals Inc.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Nisha Jain, MD

Division of Hematology

OBRR/CBER/FDA

 


TABLE OF CONTENTS

PAGE

 

1.0       GENERAL INFORMATION                                                                          3  

                        PRODUCT NAME

                        PRODUCT COMPOSITION

                        PROPOSED INDICATION

                        DOSING REGIMEN AND

ROUTE OF ADMINISTRATION

SYNOPSIS OF MANUFACTURING PROCESS

 

2.0       EXECUTIVE SUMMARY                                                                               7

 

3.0       INTRODUCTION AND BACKGROUND                                                    9

 

4.0       REGULATORY BACKGROUND                                                                11

 

5.0       BASIS FOR LICENSURE                                                                               12

 

6.0       CLINICAL OVERVIEW                                                                                 12

 

            6.1       PHARMACOKINETIC STUDIES                                                       12  

6.2       EFFICACY AND SAFETY STUDIES                                                 13     

6.3       RESULTS OF PHASE 2 AND PHASE 3 EFFICACY AND SAFETY

            STUDIES                                                                                              15   

                                                                                                                                   

7.0       CONCLUSIONS                                                                                              22

 

8.0       QUESTIONS TO THE COMMITTEE                                                             23

 

APPENDIX 1             VIRAL INACTIVATION/REMOVAL                                   24                                                                                                   

                                                  

APPENDIX 2             DOSE ADMINISTRATION AND DOSE MONITORING

FOR PHASE 2 STUDY GTC AT III 01002                             25                                       

                                                                          

APPENDIX 3             DOSE ADMINISTRATION AND DOSE MONITORING

FOR PHASE 3 STUDY GTC AT III  012-04                           27   

                                                                                               

APPENDIX 4             ADVERSE EVENTS                                                                29

1.0       GENERAL INFORMATION

 

 

PRODUCT NAME               

 

ESTABLISHED NAME:                   Antithrombin III (recombinant)

 

PROPOSED TRADE NAME:           ATryn®

 

PRODUCT COMPOSITION (from the Applicant’s proposed label):

ATryn®, Antithrombin III (Recombinant), for Injection is a nanofiltered, sterile, terminally heat-treated lyophilized dosage form. It is a 432 amino acid glycoprotein with a molecular weight of approximately 57,215 Daltons. The molecular formula is: C291H3457N5830656S18.

 

Recombinant antithrombin III (rATIII) is produced by recombinant DNA technology using genetically engineered goats into which the gene for human antithrombin has been introduced along with a mammary gland specific promoter, which directs expression of the protein in the milk. The goats in which rATIII is produced are USDA certified scrapie-free, and specific pathogen-free.

 

Using a reference standard calibrated against a World Health Organization international standard for antithrombin III concentrate, each vial of ATryn contains 1,750 international units (IU) of antithrombin III (250 mg of rATIII).  The product is formulated with citrate, chloride, and glycine, and each vial contains 100 mg glycine, 79 mg sodium chloride, and 26 mg sodium citrate. When reconstituted with 10 mL Sterile Water for Injection, the pH is 7.0. Following reconstitution, the solution may be further diluted into 0.9% sodium chloride for injection.

 

ATryn does not contain antimicrobial preservatives nor is it formulated with human plasma proteins. rATIII is affinity purified using a heparin resin.  ATryn is a purified product, and contains less than 0.0002 IU heparin per IU rATIII.

 

The purification and drug product manufacturing process have been validated to ensure removal and/or inactivation of viruses and prions. The purification and drug product manufacturing process, which include both nanofiltration and heat treatment steps, have been challenged with a panel of viruses of different types and have shown capable of minimally achieving ≥8 to ≥25.3 log10 reductions. The goats are from a closed, USDA certified scrapie-free herd. The purification process was further challenged to remove prions. The process was shown capable of achieving a ≥ 11.3 log10 reduction.

 

Manufacturer:                      GTC Biopharmaceuticals Inc. Framingham, MA 01702

 

PROPOSED INDICATION: ATryn is indicated for the prevention of peri-operative and peri-partum thromboembolic events in hereditary antithrombin deficient patients.

 

DOSING REGIMEN:            The dosage of ATryn is individualized for each patient.

The goal of treatment with ATryn is to restore and maintain functional antithrombin activity levels between 80 -120% (0.8 – 1.2 IU/mL) of normal to prevent thromboembolic

events during peri-opertive and peri-partum period

 

Initial treatment includes a loading dose of ATryn targeting an antithrombin activity level of 100%. The initial loading dose is based on the patient’s pre-treatment functional AT activity level and body weight in kilograms.

 

Dosing Formula for (non pregnant) Patients

 

The loading dose:

Dose (IU) = [(100 - pre-treatment AT activity level in %) /2.28] x Body Weight in kg

 

The loading dose should be given as a 15 minute infusion followed immediately by initiation of the maintenance infusion.

 

The maintenance dose is administered by continuous infusion. The maintenance dose, expressed in IU/hour, is determined using the following formula:

Dose (IU/hour) = [(100 - pre-treatment AT activity level in %) /10.22] x Body Weight in kg

 

The usual maintenance dose is 4-5 IU/kg/h.

 

Dosing for Pregnant Women

The loading dose is determined using the following formula:

Dose (IU) = [(100 - pre-treatment antithrombin activity in %) / 1.25] x Body Weight in kg

 

The loading dose should be given as a 15 minute infusion followed immediately by initiation of the maintenance infusion.

 

The maintenance dose is administered by continuous infusion. The maintenance dose, expressed in IU/hour, is determined using the following formula:

Dose (IU/hour) = [(100 - pre-treatment antithrombin activity in %) / 5.43] x Body Weight in kg.

 

ROUTE OF

ADMINISTRATION:                        Intravenous

 

   POTENCY:             Each vial is labeled with the nominal potency of no less than 1750 IU/vial (250 mg/vial). Each vial contains the following excipients: 104.8 mg Glycine, 82.8 mg sodium chloride, 27.1 mg sodium citrate. ATryn is reconstituted with 10 mL of Sterile Water for Injection.

 

SYNOPSIS OF THE MANUFACTURING PROCESS:

 

The active ingredient in ATryn is a recombinant form of human ATIII that is produced in the milk of transgenic goats.  Fine details of the manufacturing process are not provided in this briefing document due to their proprietary nature.

 

Herd of transgenic goats and collection of milk (source material)

 

The transgenic goat was obtained after microinjection of the DNA expression construct (transgene) in the pro-nucleus of a goat embryo.  The transgene is composed of the cDNA of human ATIII and the regulatory elements (promoter) of the goat beta casein gene.  The latter drives the expression of ATIII in the goat mammary gland.  The selection of the first transgenic goat F0 (male founder) was based on the transgene status (DNA sequence integrity and germline transmission) and its capability to express rATIII in high quantity in the milk (induced by prolactin).

 

Goat breeding is accomplished through a combination of natural breeding and artificial insemination.  To secure continuation of the manufacture, a --(b)(4)------ transgenic animal banking system has been established, -----------------------(b)(4)------------------------------------------------------(b)(4)------comprised of qualified male and female goats, and the semen from qualified male goats.  The genetic stability of the transgene has been demonstrated up to seven generations of goats.  Qualification of goats to the production herd is based on genotyping, assessment of milk composition and content of rATIII, microbiological and adventitious agent screening of the milk pools, and examination of animal health.  Source material (milk) is collected from qualified does, frozen, and shipped to ------(b)(4)--------------------------- (contract manufacturer for BDS) facility for further processing. 

 

In order to optimize the consistency of the source material, which shows certain variability with regards to the amount of milk components and characteristic of ATIII molecule, a milk pooling strategy has been incorporated.  Compositional analysis of batches demonstrated that acceptable level of consistency has been achieved.

 

Purification of ATryn bulk drug substance (BDS)

 

Purification begins with thawing, pooling and clarification of the source material, followed by filtration steps, three chromatography columns, and filtration though a virus retention nano-filter.  The BDS is formulated before for the final production steps.

 

The viral filtration step was added in 2006 and did not negatively affect product safety and efficacy as demonstrated in clinical trials.

 

Analysis of data from three consecutive batches of BDS and their in-process controls was performed to support the consistency of the manufacture process.

 

Removal of milk-derived impurities by the purification process was adequately validated by analyses of milk production pools and BDS batches derived from the validation studies or designated for the commercial distribution.  Suitably validated analytical assays were used to demonstrate the efficient removal of these impurities.

 

Characterization of structure and function

 

The structure of rATIII is consistent with published data on plasma-derived ATIII (pdATIII) with N-terminal variability in the first two or three amino acids (£ 10% of the product) but larger truncations have not been detected.  Four methionine residues have been identified as potential oxidation sites.

 

Recombinant ATIII and pdATIII are glycosylated with each containing 3-4 N-linked carbohydrate moieties.  However, they differ in monosaccharide composition and oligosaccharide structure.  These differences account for the increased affinity (about fourfold) of rATIII to heparin compared to pd-ATIII.  The functional in vitro assays for ATIII activity are not affected since they are performed in the presence of excess heparin.

 

BDS specifications

 

Specifications and validation of analytical methodology provided for the control of BDS are deemed acceptable.  Each batch of BDS is tested for identity, purity, and potency.  The specifications are justified by results from conformance batches, nonclinical and clinical studies.  All routine methods used as control or release test of starting materials, process intermediates, drug substance, drug product, and stability samples were validated as appropriate.

 

Milk contaminants are known allergens and may be present in trace amounts in the product.  Therefore, they are monitored with a variety of assays.  A Warning and Precaution statement will be included in the product label to preclude patients with hypersensitivity to goat proteins or goat milk components.

 

Manufacture of Final Drug Product (FDP)

 

The final product is manufactured by -------------------(b)(4)-------------------------------, The --------(b)(4)---------Netherlands where the product is aseptically filled, lyophilized, and subjected to a terminal sterility and viral inactivation step by heat treatment.  Viral clearance data for various manufacturing steps of ATryn® are summarized in Appendix 1.

 

The analytical control of the finished product is similar to that performed on the BDS.  The in vitro assay of product potency is based -----------------------------(b)(4)----------------------------------------------(b)(4)--------------------------------.  The assay is consistent with the assay routinely used to measure the potency of plasma-derived (pd) ATIII.  The internal reference standard was calibrated against the WHO IS ATIII concentrate and the potency of ATryn is expressed in IU.

 

Control of Adventitious Agents

 

Viral safety and control of scrapie agents are adequately addressed.  The pathogen safety of ATryn relies on the control of goats, starting material (milk), and documented clearance of pathogens by the manufacturing process.

 

The goat herd is closed and comprises of selected animals with limited origins (USA and New Zealand).  The GTC goats are scrapie-free certified by the United States Department of Agriculture (USDA).  The herd is vaccinated and monitored for general health status and pathogens.  The milk pools used for the purification of ATryn are tested for pathogens.  The validation for clearance rates of enveloped and non-enveloped viruses by the manufacturing process is satisfactory.  Furthermore, the removal rates of scrapie agents for some steps of the production process were demonstrated.

 

Stability of ATryn Final Drug Product

 

Stability studies were performed on three (3) lots of ATryn stored at 2oC - 8oC.  Results of the studies support the shelf life of the product of 30 months.

 

Based upon in-use stability studies, the reconstituted product should be administered within 8 hours of preparation.

 

2.0       EXECUTIVE SUMMARY

 

This briefing document contains a summary of FDA’s evaluation of efficacy and safety data provided by GTC Biotherapeutics Inc. to support approval of ATryn® indicated for the prevention of peri-operative and peri-partum thromboembolic events in hereditary antithrombin deficient patients.

 

The dosage of ATryn® is individualized for each patient. The goal of treatment with ATryn is to restore and maintain functional antithrombin activity levels between 80 -120% (0.8 – 1.2 IU/mL) of normal to prevent thromboembolic events. The proposed release specification potency is (b)(4) IU/vial, with a shelf-life of 2 years when stored at 2°C–25°C (36°F-77°F).

 

The Biologics Licensing Application (BLA) contains the following studies conducted under IND ---(b)(4)----, that are adequate and well-controlled to support  the proposed indication

 

  1. GTC AT III 01002:  Phase 2 study to assess the incidence of  thromboembolic events following prophylactic intravenous (iv) administration of antithrombin (rhAT) to hereditary antithrombin (AT) deficient patients in high-risk situations compared to the historical control (see below)

 

  1. GTC AT HD 012-04:  Phase 3 study  multicenter, multinational study to assess the safety and efficacy of rhATIII  in hereditary antithrombin (AT) deficient patients in high-risk situations for thromboembolic events compared to the historical control (see below)

 

  1. GTC AT HD-R 013-04: Historical cohort study to assess the incidence of

thromboembolic events following prophylactic intravenous administration of plasma derived antithrombin to hereditary antithrombin (AT) deficient patients in high-risk situations.

 

  1. AT III-009-00: A  comparative single-dose Pharmacokinetic study of rhAT III with

Plasma derived ATIII in hereditary antithrombin (AT) deficient patients

 

Efficacy

 

Efficacy was evaluated in studies GTC AT III 01002 and GTC AT HD 012-04 for prevention of peri-operative and peri-partum thromboembolic events in hereditary antithrombin deficient patients. The data from the two studies demonstrate similar efficacy in preventing peri-operative and peri-partum thromboembolic events in congenital deficient patients when compared to historical data for patients treated with plasma derived ATIII. The studies conducted support the dosing recommendations for surgical and pregnant patients.

 

Immunogenicity

 

Immunogenicity to ATryn™ was assessed by measuring serum antibodies against ATIII, plasma derived ATIII, goat ATIII and goat milk proteins at baseline and at various times after dosing up to 90 days.   Development of antibodies was not reported in any patient in the two studies listed above and the other supportive studies. However, data on repeat exposure with the product is very limited.  Only one patient with hereditary ATIII deficiency received the product a second time.  That patient did not develop any antibodies.   The immunogenicity of the product on repeat exposure will be further evaluated in a post- marketing study.

 

Safety

 

The safety profile of ATryn when used for prevention of peri-operative and peri-partum thromboembolic events in hereditary antithrombin deficient patients at the recommended dose schedule is acceptable.  Bleeding (intra-abdominal hemorrhage in a pregnant female and hemarthrosis in a surgical patient)   was reported in two subjects. Concomitant administration of heparin may enhance the pharmacodynamic action of ATryn. Both the patients recovered without sequelae. There were no deaths and no adverse events that led to study discontinuation.   Safety with repeat exposure will be evaluated in a post marketing study.

 

Conclusions

 

ATryn at the recommended dose is effective in reducing prevention of peri-operative and peri-partum thromboembolic events in hereditary antithrombin deficient patients.  The safety profile appears to be acceptable.  The immunogenicity on repeat exposure remains to be evaluated.

 

3.0       INTRODUCTION AND BACKGROUND

 

Antithrombin (ATIII) is a 58 kDa single chain glycoprotein that contains 423 amino acids and has a carbohydrate content of about 15%. The protein has 3 disulfide bridges and 4 N-linked glycosylation sites (Asn 96, 135, 155, and 192).

 

ATIII is a serine protease inhibitor that is the principal inhibitor of the blood coagulation serine proteases thrombin (Factor IIa) and Factor Xa, and to a lesser extent, Factors IXa, XIa, XIIa, trypsin, plasmin, and kallikrein. ATIII neutralizes the activity of thrombin and other serine proteases by forming an irreversible 1:1 stoichiometric complex between enzyme and inhibitor. In the presence of heparin, the normally slow formation of complex becomes dramatically accelerated.  The ability of ATIII to inhibit thrombin can be enhanced by more than 1000 fold when ATIII is bound to heparin. The thrombin-antithrombin complex (TAT) is rapidly removed by binding to a receptor in the liver. The half-life of TAT complex is less than 5 minutes in humans. ATIII is also referred to as heparin cofactor. Localization of a fraction of the ATIII on the endothelial surface, where enzymes of intrinsic coagulation cascade are commonly generated, enables ATIII to rapidly neutralize these activated clotting factors and protect natural surfaces against thrombus formation.

 

The mean concentration of ATIII in human plasma is about 0.1 g/L. The biological activity of 1mL of pooled human plasma in a thrombin or FXa inhibition assay is defined as 1 IU/mL. Normal ranges for the assay are between 80% and 120%.

 

            Hemophilia (2008)14, 1229-1239

           

Congenital ATIII deficiency (Hemophilia 2008, 14, 1229-1239: Patnaik and Moll)

 

Antithrombin (AT) deficiency was first described in 1965 by Olav Egeberg in a family in which several family members had venous thromboembolism (VTE). Egeberg also established the deficiency to be an autosomal dominant disorder. Most cases are heterozygous. Homozygosity for AT deficiency is always fatal in utero. Inherited AT deficiency is uncommon with prevalence rates for AT deficiency of 1 in 2000- 5000 in the overall population. The types of AT deficiency are shown in the table below:

 

 

 

Patients with congenital deficiency present with thromboembolic events (TE).   TE in hereditary AT deficient patients are uncommon prior to puberty but increase thereafter, particularly during periods of high risk, such as pregnancy, surgery, or bed rest. Hereditary AT deficiency causes a life-long increased risk of venous thromboembolism and

up to 70% of cases do develop a venous thromboembolic event (VTE) during their lives

Often VTEs are recurrent and may be life-threatening. The risk of development of VTEs as compared to the normal population in these situations is increased by a factor of 10 to 50. Failure to properly treat hereditary AT deficient patients, especially during high risk situations such as surgery or trauma or for pregnant women, during the peri-partum period, may result in VTE. Asymptomatic hereditary AT deficient patients generally do not require anticoagulant prophylaxis, except in settings of increased risk. Hereditary AT deficient individuals with a history of one thrombosis are treated with  chronic oral anticoagulant prophylaxis.

 

4.0       REGULATORY BACKGROUND

 

There is currently one plasma derived Antithrombin III product licensed in the US: Thrombate III® manufactured by Talecris Biotherapeutics.

 

The following summarizes the regulatory chronology of this BLA:

 

March 2001                             Pre-IND Meeting with sponsor to discuss clinical development of the product for prevention of thrombosis in hereditary AT deficient patients

 

December 2002                       Second pre-IND meeting for the above indication

 

March 2003                             IND received by OTRR, CBER

 

August 2003                           IND transferred to OBRR, CBER

 

August 2003                           IND placed on Clinical Hold because of deficiency in the clinical protocol and safety concerns

 

November 2003                      Clinical Hold removed

 

April 2004                               GTC requests a pre-BLA meeting. CBER advises that a second study will be needed to support licensure.   CBER also advises GTC to develop a sensitive assay for evaluation of immunogenicity.

 

July 2004                                 Phase 3 protocol submitted.

 

November 2005                      Phase 3 study initiated

 

August 2006                           Approved by EU for prevention of peri-operative                                                                 thromboembolism in hereditary deficient patients

 

October 2007                          Pre-BLA meeting

 

November 2007                      Orpahn drug designated

 

December 2007                       Fast track designation granted.

 

January 2008                           Rolling BLA submitted

 

August 2008                           Clinical module of the BLA submitted and PDUFA timeline initiated

 

August 2008                           Priority review granted

 

February 2009                         Regulatory action due date

 

 

5.0       BASIS FOR LICENSURE

 

The applicant conducted Phase 2 and 3 historically controlled studies to evaluate  prevention of peri-operative and peri-partum thromboembolic events in hereditary antithrombin deficient patients. A total of 31 patients were enrolled in the ATryn arm and 35 matched controls were selected from patient records obtained from 20 international sites. 

 

In addition, the applicant conducted a population pharmacokinetic analysis of Atryn and compared it to human plasma-derived antithrombin in 15 congenital deficient patients

 

6.0              CLINICAL OVERVIEW

 

6.1       PHARMACOKINETIC STUDIES:

 

AT III-009-00: Randomized Pharmacokinetics of AT III in Patients with hereditary AT III deficiency receiving two doses 50 and 100 IU/kg:

 

This was an open-label, single dose pharmacokinetic study in male and female patients (≥ 18 years of age) with hereditary AT III deficiency.  The patients received either 50 (n = 9 all females) or 100 (n = 6, 2 males and 4 females) IU/kg ATryn intravenously.  Blood samples were collected before the administration of the drug and at 5, 10, 15, 30, 45, and 60 minutes and at 2, 4, 6, 8, 24, 48, and 72 hours.  The clearance and half-life of ATryn were 9.6 and 7.2 mL/hr/kg and 11.6 and 17.7 hours following 50 and 100 IU/kg dose, respectively. The incremental recovery was 2.07 ± 1.54 %/IU/kg body weight.

 

AT III-009-00: Population pharmacokinetic analysis of recombinant human antithrombin and comparison to human plasma-derived antithrombin:

 

The objective of this investigation was to compare the pharmacokinetics of ATryn and plasma-derived antithrombin (pdAT) using population-pharmacokinetic approach.

 

The pharmacokinetics of ATryn were evaluated in 15 patients with congenital antithrombin deficiency following a short intravenous infusion of 50 or 100 IU/kg.  The pharmacokinetics of pdAT were evaluated from a study performed in 1984 in the USA in 8 patients with congenital AT deficiency, following intravenous infusion of 25 to 225 IU/kg pdAT.  The following Table summarizes the PK parameters of the two products.

 

A PK comparison between ATryn and plasma derived AT

Parameters

rhAT

pdAT

CL (mL/hr/kg)

9.5

1.3

Half-life (hrs)

10.2

91.2

Vss (liters)

7.7

9.8

 

Conclusions: Plasma-derived AT has almost a 9-fold longer half-life and 7-fold slower clearance than ATryn.

 

6.2       EFFICACY AND SAFETY STUDIES

 

GTC AT III 01002:  “Phase 2 study to assess the incidence of thromboembolic events following prophylactic intravenous (iv) administration of antithrombin (rhAT) to hereditary antithrombin (AT) deficient patients in high-risk situations.”

 

This was a single arm, multicenter, multinational, open-label study with blinded evaluation of the ultrasonographic images.  15 hereditary AT deficient patients (documented AT activity ≤ 60% of normal and with previous history of thromboembolism) scheduled for surgery, Caesarean section, or vaginal delivery  qualified for the study were treated prophylactically with ATryn. Dosing with ATryn was individualized to increase and maintain target AT activity levels between 80% and 120% of normal. Functional AT activity levels were used to monitor and adjust dosing.

 

ATryn administration to patients scheduled for surgery and patients scheduled for

Caesarean section or delivery was initiated approximately 24 hours before the planned

procedure and continued for a minimum of 3 days. ATryn therapy was continued, until effective chronic anticoagulation therapy was established and the patient was mobilized and ready for hospital discharge (See APPENDIX 2).

 

In pregnant patients not scheduled for Caesarean section or induction of delivery,

treatment was initiated only when the patient was hospitalized and in active labor.

Treatment of these patients was also continued for a minimum of 3 days and continued until effective chronic anticoagulation therapy was established and the patient was mobilized and ready for hospital discharge.

 

A blinded, independent determination of the incidence of acute DVT  based on duplex ultrasound examination was the primary measurement of the outcome of treatment with ATryn. Standardized duplex ultrasound examination of the lower extremities was used to establish the presence or absence of acute DVT. Duplex ultrasound studies were performed and interpreted by qualified specialists within the same hospital/institution on a real time basis for the timely and appropriate clinical care of the patient. Venography could be used, when clinically indicated, if the study investigator felt that duplex ultrasound results were inconclusive. For other TE relevant diagnostic modalities were used.

 

GTC AT HD 012-04:  “Phase 3 study multicenter, multinational study to assess the safety and efficacy of antithrombin III in hereditary antithrombin (AT) deficient patients in high-risk situations for thromboembolic events”

 

The trial design for this study was similar to the phase 2 study.  This was a single arm, open-label multi-center, multinational study in 18 patients. Congenital AT deficient patients scheduled for surgical procedures (with personal histories of  TE and documented AT levels less than 60%) and pregnant patients were enrolled in the study.

 

Dosing with ATryn was to be individualized to increase and maintain target AT activity levels between 80% and 120% of normal. Functional AT activity levels were used to monitor and adjust dosing. For elective procedures (i.e. non-pregnant surgery patients and pregnant patients scheduled for Caesarean section or delivery induction), treatment with ATryn was initiated up to 24 hours prior to the scheduled procedure. For pregnant patients not scheduled for Caesarean section or delivery induction, treatment with ATryn was started as soon as they were admitted to the hospital and active labor had begun.  The dosing algorithm was revised for pregnant patients based on phase 2 results (See APPENDIX 3).

 

Administration of ATryn was continued for a minimum of 3 days for all study patients and

continued until effective chronic anticoagulation therapy  was established  and the patient was mobilized and ready for hospital discharge. The protocol-specified maximum duration

of treatment was limited to 14 days.

 

The incidence of thromboembolic events was assessed clinically in all patients who were treated with ATryn. Signs and symptoms indicative of the occurrence of a thromboembolic event were monitored during treatment with ATryn and up to and including 7 days after cessation of ATryn treatment. If signs and symptoms indicated the occurrence of a thromboembolic event appropriate diagnostic tests were performed to confirm or exclude the presence of the event.

 

GTC AT HD-R 013-04: Historical cohort study to assess the incidence of

thromboembolic events following prophylactic intravenous administration of plasma-derived antithrombin to hereditary antithrombin (AT) deficient patients in high-risk situations. Both studies (GTC ATIII 01002 and GTC ATHD 012-04) were compared to the historical control.

 

This was an international, multi-center, prospectively designed retrospective cohort study of hereditary AT deficient patients who had a history of thromboembolic events, an elective procedure performed since 1 January 1997 that placed them at high risk for the occurrence of a thromboembolic event, and at that time, were treated prophylactically with intravenous administration of plasma-derived AT for a minimum of 2 days.

 

Approximately 5 to15 sites were planned for participation in the study. All

eligible study sites had a listing or automated medical record system that identified patients

who had hereditary AT deficiency and/or those patients who had received plasma AT during high-risk elective procedures since 1 January 1997.

 

All the patients identified were selected. A minimum of 35 up to a maximum of 70 patients identified from the listing or automated medical record system of all patients eligible patients at the sites were included in the study. The eligibility criteria were the same as for the study conducted with ATryn.   Clinical outcomes in terms of TE were noted in the case report form.

 

Statistical Methods for Determining the Efficacy End-Point

 

The statistical approach used was to establish non-inferiority by comparing the incidence of any TE event with plasma-derived ATII vs. ATryn (results were combined from Phase 2 and 3 studies). The non inferiority margin was set at 20%. Use of a one-sided lower confidence bound, instead of a confidence interval, consistent with use of a one-sided test for a non-inferiority study was adopted.  The 95% confidence interval based on the exact (Clopper-Pearson) method for the proportion of patients with presence of DVT for both groups was presented.

 

Safety Monitoring

 

In both studies the patients were evaluated for laboratory parameters of coagulation (INR, aPTT, and anti-Xa activity) and immunogenicity (up to 90 days after treatment). Active assessment of any bleeding complications was performed and included a brief physical examination, hemoglobin and hematocrit measurements, and urinalysis every day during ATryn administration through the last day treatment. In addition, blood serum samples were collected to allow for retrospective infectious or immunological evaluations in the future, if indicated.

 

6.3       RESULTS OF PHASE 2 AND PHASE 3 EFFICACY AND SAFETY STUDIES

 

Study Objectives and Endpoints

 

The objective of the two studies was  to assess the  incidence of thromboembolic events  following prophylactic IV administration of ATryn   in situations associated with a high risk for thromboembolic events and  to evaluate  the safety of ATryn in patients with hereditary AT deficiency.

 

The primary endpoint of the two studies (combined) was non-inferiority of incidence of TE during and within seven days of treatment with ATryn compared with a historical cohort control of comparable patients treated with plasma derived ATIII.

 

Results of the Phase 2 AT III 01002 study:

 

FDA analysis consists of intent to treat population defined by all patients who received at least one dose of ATryn.  Of the 14 patients enrolled, one patient had baseline a DVT but had   received treatment with ATryn as diagnosis of baseline DVT was made after the patient had been treated. However this patient is excluded in the efficacy analysis for prevention of thrombosis. Of the 13 patients 5 were treated peri-operatively and 8 were treated during the peri-partum period.   All 13 patients had a prior history of TE. Patients’ ages ranged from 21 to 74 years with a mean of 36.7 years. The mean baseline AT activity level for surgical patients was 50% and the median was 53% and for pregnant patients the mean AT levels were 46% and the median was 45%.

 

All 13 patients were observed for clinical signs and symptoms of thromboembolic events. One patient had lower leg edema and venous distension for several days during Atryn treatment and another patient had venous distention before, during and following the dosing period. Both the patients were negative for acute DVT by ultrasound examination.

 

All patients were evaluated for acute DVT by duplex ultrasonography examinations, which were interpreted both locally as well as under blinded conditions centrally by an independent imaging laboratory. Acute DVT was identified by both the central and local readers for one surgery patient during treatment, i.e. a treatment failure.  This patient received ATryn for a total of nineteen days and was diagnosed with DVT of left  the popliteal vein and the superficial femoral vein on the thirteenth day of ATryn treatment based on an unscheduled Doppler ultrasound done when the patient presented with signs and symptoms.  The treatment with ATryn maintained the targeted AT activity level between 80% to 120% of normal at all times, except immediately following surgery when AT activity was measured at 69%.  It is possible that the clot formation had initiated during the time when AT activity levels were 69% of normal and propagated despite bringing the AT activity levels to 80% to 120% of normal by bolus administrations (8 boluses).  It appears that ATryn may be not effective in clot resolution at the recommended target levels.  In another patient a   superficial crural vein thrombosis was identified by only one of the central readers. This was not considered a treatment failure as 2/3 central readers and the local readers identified it as chronic changes. FDA reviewer also considers it to be a local chronic change also present at baseline.

 

Diagnostic imaging was performed in three patients to exclude the presence of

suspected thromboembolic events [to rule out pulmonary embolism (PE) and cranial thrombosis]. All testing for these patients was negative for the presence of any

thromboembolic event.

 

Administration of ATryn according to the protocol-defined dosing and monitoring scheme

resulted in adequate control of AT activity levels within the desired 80 to 120% range in

four of the five surgical patients. Four of the 5 surgery patients received an average of 2.5 (range 1-8) bolus ATryn administrations during the course of their treatment period (see table below).

 

AT activity levels dropped below the lower limit of normal for all 5 surgery patients when rhAT administration was discontinued. Central laboratory AT activity levels at 30, 60, and 90 days following discontinuation of rhAT treatment were above or near baseline AT activity levels documented just prior to initiation of rhAT treatment.  In all patients anti-coagulation was established by heparin prior to cessation of ATryn therapy.

 

For the 8 delivery patients, administration of ATryn according to the protocol defined

dosing and monitoring scheme resulted in adequate control of AT activity levels within

the desired 80 to 120% range. Bolus dosing increased AT activity levels to within or above the normal range with the exception of 3 of the 8 delivery patients  who required between 12-15 dose adjustments to keep the levels between 80-120% as specified in the dosing regimen schedule. Because of the numerous dose adjustments needed in one third of the pregnant patients, FDA advised the sponsor to revise the dosing algorithm for these patients in the phase 3 study (see below)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ATryn treatment duration, rhAT dose administration and dose adjustments

 

Group/Patient

Number

Treatment Duration (days)

Total loading doses (IU/kg)

Dose per day

(IU/kg/day)

Dose adjustments

Surgery group

 

---(b)(6)----

---(b)(6)----

---(b)(6)----

---(b)(6)----

---(b)(6)----

 

 

12

8

13

19

10

 

 

50.0

47.1

38.2

35.1

21.0

 

 

166.0

157.1

79.5

179.9

113.7

 

 

3

4

4

8

1

Pregnant Group

---(b)(6)----

---(b)(6)----

---(b)(6)----

---(b)(6)----

---(b)(6)----

---(b)(6)----

---(b)(6)----

---(b)(6)----

---(b)(6)----

 

 

10

3

3

3

4

4

5

3

3

 

48.6

21.0

26.9

27.2

19.7

23.7

81.4

25.3

20.3

 

293.0

222.0

331.6

207.0

249.5

286.5

451.7

167.0

277.4

 

12

2

4

14

2

2

6

1

15

 

IU= international units

 

In conclusion, one out of thirteen patients developed a DVT and was considered a treatment failure. This study was not considered for licensure because there was no comparator for efficacy and the safety data especially with regards to thrombogenicity were insufficient.

 

Results of the Phase 3 GTC AT HD 012-04 study:

 

A total of 23 patients were enrolled in the study with 18 (78.3%) of the 23 patients receiving treatment with ATryn. All 18 (100.0%) ITT population patients completed the study.  The reasons for five of the enrolled patients who were not included as ITT population of the study were: (i) ineligible due to DVT at baseline, (ii) went into

spontaneous labor, (iii) spontaneous amniorrhexis, (iv) fetal Doppler results were pathological hence withdrew consent and (v) signed an informed consent form  and had some study procedures performed and then withdrew consent.

 

In the safety and the ITT population, six of the ATryn-treated patients were non-pregnant surgery patients and 12 were pregnant patients. The Per Protocol population was comprised of 6 non-pregnant surgery patients and 11 pregnant patients. One patient was not included in the Per Protocol population because the patient’s treatment started after delivery, instead of before delivery as specified in the protocol.

 

The mean patient age was 37.2 years (21-62 years). The mean screening AT activity level  was 50.9% and ranged from 29.0% to 65.7% with Although some screening AT activity levels were above 60%, patients  met all the inclusion criteria, and had historical levels confirming hereditary AT deficiency.

 

Concomitant medications for all patients included the heparin group of anticoagulants.

 

For the primary efficacy endpoint, the Intent-to-Treat Population (ITT) was defined as those patients who received ATryn and had at least one follow-up assessment after initiation of treatment with ATryn. The ITT population included 6 non-pregnant surgery patients and 12 pregnant patients.

 

The Per Protocol Population included those patients who received ATryn and met inclusion criteria of a personal history of venous thromboembolic events and a history of congenital deficiency that included 2 or more plasma AT activity values ≤ 60% of normal, and received at least 3 (calendar) days of treatment with ATryn with at least one follow-up.

The Per Protocol population included 6 non-pregnant surgery patients and 11 pregnant

patients.

 

Safety Population: This population included all patients who received at least 1 dose of

ATryn. The Safety population included 6 non-pregnant surgery patients and 12 pregnant

patients.

 

The efficacy of ATryn for the prophylaxis of thromboembolic events in

surgical and pregnant patients with congenital deficiency undergoing  medical high risk  procedures was evaluated by assessment for clinical signs and symptoms of  any thromboembolic events. This was followed by the appropriate diagnostic testing. The occurrence of a thromboembolic event was confirmed if symptoms occurred and  diagnostic testing was positive.

 

During treatment and during the follow-up period of 7 days after cessation of treatment with ATryn, no thromboembolic events occurred in the intent to treat population (n = 18). The patients included in this study all had significant prior personal histories of venous thromboembolic events which elevated the risk for recurrence of such events in this study.

 

On the basis of the efficacy results, it is concluded that ATryn is effective in preventing potentially life-threatening thromboembolic events in patients with congenital deficiency during the peri-operative or peri-partum period.

 

There were 2 venous thromboembolisms reported in the study after the 7-day post-treatment follow-up period. A DVT was reported 11 days after discontinuation of

treatment with ATryn and a PE occurred 14 days after stop of ATryn treatment. Given the short half-life of ATryn (approximately 10 hours), it is not expected that ATryn will have a beneficial effect that long after stopping treatment. It can, therefore, be concluded that these events were not due to a lack of efficacy of ATryn, but due to the potential lack of efficacy of the anticoagulant medication being administered at the time of each event. 

 

In conclusion, the data from the current study demonstrates the efficacy of ATryn for the prevention of thromboembolic events in congenital deficient patients in high risk situations and the effectiveness of the dosing formula for both surgical patients and pregnant women (shown in graph and table below)

 

 

Treatment duration and dose administration and dose adjustments

 

Group

Treatment Duration (days)

Total loading doses (IU/kg)

Dose per day

(IU/kg/day)

Dose adjustments

 

Surgery group

N=6

Mean

Median

Range

 

 

 

 

7

3

3-14

 

 

21.6

19.2

13.5-34.4

 

 

 

37.8

21.2

15-78.5

 

 

2.5

2.0

1-6.0

Pregnant Group

N=12

Mean

Median

Range

 

 

4.4

3.6

1-14.0

 

 

36.3

35.5

13.0-57.6

 

 

38.9

30.2

7.2-139.9

 

 

1.5

1.0

0.0-6.0

 

Please note with the revised dosing algorithm for pregnant patients, the number of dose adjustments needed was significantly reduced compared to the Phase 2 Study.

 

Conclusion of Overall Efficacy:

 

Patients for the control group (pdATIII) were matched, as for as possible, for demographics, medical/surgical history, history of prior TEs, surgical procedure, baseline AT activity levels  and concomitant medication with the ATryn group. The two studies conducted with ATryn, when pooled together, show that Atryn is as effective as plasma derived ATIII in preventing peri-operative and peri-partum thromboembolism in congenital ATIII deficient patients when analyzed by prespecified statistical parameters and methods (see table below)

                                                           

 

Test (31)

Control (35)

TE Outcome

 

 

Positive

1

0

Negative

30

35

                                   

                       

 

 

 

P-value

 

95% Confidence Interval

(P2-P1)

Type

1-sided

2*1-sided

Lower Limit

Upper limit

Asymptotic

0.1422

0.2843

-0.1634

0.0698

Exact

0.2401

0.4802

-0.167

0.0778

 

The primary efficacy endpoint is the incidence of any thromboembolic event after the start of treatment (pdAT or rhAT) and within 7 days following discontinuation of treatment. Clopper Pearson exact 95% confidence interval for the proportion of patients with a thromboembolic event is presented for each treatment group, as well as the exact 95% lower confidence bound for the difference between treatments. Non-inferiority

is demonstrated as the lower 95% confidence bound of the difference  is

-0.20.

                                   

Safety:

 

During dosing, five (83.3%) of the six surgery patients and nine (75.0%) of the 12 pregnant patients experienced one or more TEAE of mild or moderate severity. Four (22.2%) of the 18 study patients experiencing a TEAE were rated severe (shown below). The AE rated as severe included one surgery patient and three pregnant patients:

 

Table showing AEs that were severe in intensity

Patient

Type of AE

Relationship to ATryn

Surgery

Severe headache

Not related

Pregnant

 Dilutional anemia with no evidence of bleeding. 

Muscle spasm

Not related

 

Not related

Pregnant

Enterobacter sepsis

Not related

Pregnant

Vaginal tear

Not related

 

 

TEAE occurring in two or more patients treated with ATryn due to all causes are presented below:

 

Body System/ preferred term

TEAE incidence

Number of events

Total number of patients

18 (88.9)

63

Anemia

3  (16.7)

3 (4.8)

Vaginal laceration

3 (16.7)

3 (4.8)

Non cardiac chest pain

2 (11.1)

2 (3.2)

Edema peripheral

2 (11.1)

2 (3.2)

Urinary tract infection

2 (11.1)

2 (3.2)

Post procedural hemorrhage

2 (11.1)

2 (3.2)

Headache

2 (11.1)

5 (7.9)

Syncope

2 (11.1)

2 (3.2)

Hematoma

2 (11.1)

2 (3.2)

 

Immunogenicity:

 

No patients developed anti ATIII antibodies. Data on repeat exposure to the product is very limited and is being evaluated in post marketing studies.

 

7.0       CONCLUSIONS

 

ATryn has been shown to be efficacious, using the recommended dosing guidelines, for prevention of peri-operative and peri-partum thromboembolic events in hereditary antithrombin deficient patients. Careful monitoring of AT activity levels during treatment is recommended. The safety profile appears to be acceptable.

 

 

 

 

 

 

 

 

 

8.0       QUESTIONS TO THE COMMITTEE

 

Q1

 

Do the data show safety and efficacy of the product in preventing peri-surgical and peri-partum TE events in congenital ATIII deficient patients?

 

a)      Is the safety profile acceptable?

b)      Is rATIII effective in preventing TE in non-pregnant surgical subjects and in pregnant subjects during the peri-partum period?

 

Q2

 

Should post-marketing studies be performed to assess safety and immunogenicity after repeat dosing?

 

 

 

 

 


                                                        APPENDIX 1      

 

 


APPENDIX 2

 

DOSE ADMINISTRATION AND DOSE MONITORING FOR PHASE 2 STUDY GTC AT III 01002

For a patient with a pretreatment baseline AT activity of X%, the dose required to increase

and maintain the AT activity level at 100% will be as follows:

 

Loading Dose (IU) = ((100 – X)/2.28) x Patient Weight

(Loading dose in international units equals 100 minus ‘X’ divided by 2.28, then multiplied

by patient weight (in kg), where ‘X’ is the patient’s pre-dose AT activity level.)

The loading dose should be given as a 15 minutes infusion immediately followed by the

maintenance dosing. For easier programming of the infusion pump, the calculated bolus dose can be multiplied by 4 (four) to obtain the IU/h to be given for a period of 15 minutes.

 

Maintenance Dose (IU/day) = ((100 – X)/0.426) x Patient Weight

(Maintenance dose in international units per day equals 100 minus ‘X’ divided by 0.426,

then multiplied by patient weight (in kg), where ‘X’ is the patient’s pre-dose AT activity

level.)

 

Therapeutic monitoring and Dose Adjustment:

After the start of the maintenance dose infusion, blood for AT activity levels should be

drawn at 0.5 hour (i.e. this is 45 minutes after the start of the loading dose infusion). Based

on the result of this AT activity level, the infusion rate (and consequently the dose) should be adjusted using the following guideline:

1.         If the AT activity level is between 80% and 120%, no dose adjustment is needed.

Take an AT activity level 4 hours calculated from the time of the previous AT activity blood draw.

2.         If the AT activity level is less than 80%, increase the maintenance infusion rate by

50% and take a blood AT activity level 0.5 hour after the infusion rate adjustment.

3.         If the AT activity level is greater than 120%, decrease the infusion rate by 30% and

take a blood AT activity level 0.5 hour after the infusion rate adjustment.

 

When the next AT activity level is available, based on these results the dose will be adjusted again using the following guideline:

1.         If the AT activity level is between 80% and 120%, no dose adjustment is needed.

In case this is the second consecutive AT activity level that is within the target

range, next blood sample should be taken at least every 24 hours afterwards

(calculated from the start of treatment) for the duration of treatment with rh AT.

In case this is the first AT activity level that is within the target range, take an AT

activity level 4 hours calculated from the time of the previous AT activity blood

draw.

2.         If the AT activity level is less than 80%, increase the maintenance infusion rate by

50% and take a blood AT activity level 0.5 hour after the infusion rate adjustment.

3.         If the AT activity level is greater than 120%, decrease the infusion rate by 30% and

take a blood AT activity level 0.5 hour after the infusion rate adjustment.

 

This cycle of AT activity checking will be repeated until there are two consecutive samples that show an activity in the target range of >80% and <120%, and at least every 24 hours afterwards (calculated from the start of treatment) for the duration of treatment with rh AT.

 

It is possible that the procedure or delivery will influence AT activity levels. Therefore, an additional check of the AT activity level should be done approximately one hour after the surgery or delivery. In case the activity level is below 80% a 15 minutes bolus infusion of AT can be given to quickly restore the AT activity level. The dose can be calculated with the formula:

 

Bolus Dose (IU) = ((100 – Y)/2.28) x Patient Weight

(Bolus dose in international units equals 100 minus ‘Y’ divided by 2.28, then multiplied by patient weight (in kg), where ‘Y’ is the patient’s post-surgery or delivery AT activity level.)

 

For easier programming of the infusion pump, the calculated bolus dose can be multiplied by 4 (four) to obtain the IU/h to be given for a period of 15 minutes. In order to check the effect of this, an AT activity level blood sample is recommended 0.5 hour after the bolus dose administration was stopped.

 

All administrations of rh AT will be carefully documented in the patient’s CRF.

 

 


APPENDIX 3

 

DOSE ADMINISTRATION AND DOSE MONITORING FOR PHASE 3 STUDY GTC AT HD 012-04

 

Dosing for Non-pregnant Surgical Patients

For non-pregnant surgical patients the required loading dose is determined using the following formula:

Loading Dose (IU) = [(100 – patient’s pre-treatment antithrombin activity in %) divided by 2.28] x Patient Weight in kg

 

For example, a loading dose in a non-pregnant surgical patient with a baseline AT activity of 50% would be approximately 22 IU/kg bodyweight. The loading dose should be given as a 15 minute infusion immediately followed by initiation of the maintenance infusion.

 

For easier programming of the infusion pump, the calculated loading dose can be multiplied by 4 to obtain the IU/hour to be given over a period of 15 minutes.

 

The required maintenance dose for non-pregnant surgical patients is given as a continuous

infusion and is determined using the following formula:

Maintenance Dose (IU/hour) = [(100 – patient’s pre-treatment antithrombin activity in %) divided by10.22] x Patient Weight in kg

For example, a maintenance dose in a non-pregnant surgical patient with a baseline AT activity of 50% is approximately 5 IU/kg/h. See the AT activity monitoring and dose adjustment recommendations

 

 Dosing for Pregnant Patients

For pregnant patients the required loading dose is determined using the following formula:

Loading Dose (IU) = [(100 – patient’s pre-treatment antithrombin activity in %) divided by 1.25] x Patient Weight in kg

 

For example, a loading dose in a pregnant patient with a baseline AT activity of 50% is

approximately 41.5 IU/kg bodyweight. The loading dose should be given as a 15 minute infusion immediately followed by initiation of the maintenance infusion. For easier programming of the infusion pump, the calculated bolus dose can be multiplied by 4 to obtain the IU/hour to be given over a period of 15 minutes.

 

The required maintenance dose for pregnant patients is given as a continuous infusion and is determined using the following formula:

Maintenance Dose (IU/hour) = [(100 – patient’s pre-treatment antithrombin activity in %) divided by 5.43] x Patient Weight in kg

For example, a maintenance dose in a pregnant patient with a baseline AT activity of 50% is approximately 9 IU/kg/h. The patient weight used for both the loading and maintenance dose is the actual weight of the pregnant patient just before initiation of treatment.

 

 

 

 

Therapeutic AT activity Monitoring and Dose Adjustment Guidelines (Non-pregnant

surgical and pregnant patients)

 

The maintenance dose should be adjusted on the basis of laboratory measurements of

antithrombin activity. Response to rhAT may vary in individual patients, achieving different levels of in vivo recovery and different half-lives. Frequent antithrombin activity assessments and dosing adjustments may be necessary when starting treatment and just after surgery or delivery.

 

Antithrombin activity should be checked 2 hours after initiation of the loading dose. In case the antithrombin activity is below 80% or above 120%, the maintenance infusion rate should be increased or decreased by 30%, respectively.

 

Two hours after a dose adjustment or if no adjustment was made, approximately 6 hours after the start of infusion, another antithrombin activity sample should be taken. Again, in case the antithrombin activity is below 80% or above 120%, the maintenance infusion rate should be increased or decreased by 30%, respectively.

 

Subsequently, antithrombin activity should be checked 1-2 times a day and dose adjustments made accordingly. The antithrombin activity should be maintained above 80% for the duration of the treatment.

 

All administrations of rhAT and any dose adjustments should be carefully documented in the patient’s CRF.


APPENDIX 4

 

 

 

List of Serious TEAE

 

System Organ Class

Protocol/ Patient Number

Preferred Term

Reported Term

Severity

Relation

Outcome

Gastrointestinal Disorders

 

Intra-abdominal Hemorrhage

Intra-abdominal Bleeding

Severe

Definite/ Probable

Recovered

General Disorders and Administration site Conditions

 

Pyrexia

Fever Unknown Origin

Moderate

Not Related

Recovered

Injury, Poisoning and Procedural Complications

 

Femur Fracture

Traumatic Fracture of Left Femur

Severe

Remote/ Unlikely

Recovered

Infections and Infestations

 

Enterobacter Sepsis

Septicemia Enterobacter Cloacae

Severe

Not Related

Recovered

Investigations

 

Hemoglobin Decreased

Low Hemoglobin Level

Moderate

Possible

Recovered

Musculoskeletal and Connective Tissue disorders

 

Hemarthrosis

Clinical Hemarthrosis R Knee

Moderate

Not Related

Recovered

Nervous System Disorders

 

Grand Mal Convulsions

Grand Mal Seizures

Severe

Remote/ Unlikely

Recovered

Respiratory, Thoracic and Mediastinal Disorders

 

Pulmonary Embolism

Bilateral Pulmonary Embolism

Severe

Not Related

Recovered with Sequelae

Vascular Disorders

 

Hypotension

Hypotension

Moderate

Remote/ Unlikely

Recovered

 

Wound Hemorrhage

Wound Hemorrhage

Moderate

Remote/ Unlikely

Recovered

 

Deep Vein Thrombosis

Muscular Vein Thrombosis Left Upper Leg

Mild

Remote/ Unlikely

Recovered

 

Deep Vein Thrombosis

Popliteal Non-occlusive Thrombus in RLE

Moderate

Not Related

Recovered

 

Hematoma

Hematoma

Moderate

Remote/ Unlikely

Recovered